Being about 2 m2, the skin (cutis) is the largest and most nerve-rich organ in the human body and performs numerous tasks with its layer structure of epidermis (upper skin), dermis (corium) and subcutis (lower skin). The skin protects the entire organism from pathogens or molecules, solar irradiation and drying out. In addition, however, oxygen and nutrients are absorbed via skin pores. The skin additionally serves to regulate and maintain body temperature.
As a result of a large number of different receptors—about 7 to 50 per cm2—the human skin gains the ability to register highly diverse sensory impressions, ranging from temperature sensations via pain and itching to gentle touches. Coordinative information such as the position of body parts in space is also ascertained via skin receptors. Physical and/or chemical stimuli acting upon the organism are registered by the special receptors, and the information is passed to the brain in the form of neuronal activity via the peripheral nervous system. In the epidermis, for example, the Merkel cells have been identified as mechanoreceptors for touch and pressure sensations. Further important sensors are the Vater-Pacini corpuscles in the suboutis area which react to vibrations, and Meissner's touch corpuscles or touch disks at the epidermal-dermal border which are responsible for touch sensations. Further well-developed sensory organs in the region of the epidermis are the Ruffini corpuscles (stretch receptors), and the Krause corpuscles or end bulbs (mechanoreceptors). Intraepithelial nerve endings are sensitive nerve fibers in the skin which trigger sensations of warmth, cold, pain, touch and pressure.
A nociceptor (Latin nocere: to damage) is a receptor which reacts to impending or existing injury of the body tissue. The density of nociceptors in humans is greater than that of all other skin receptors. Distribution on the surface of the body is relatively even. The change in the stimulus threshold is brought about through the release of endogenous, chemical substances which make the nociceptors more sensitive and more receptive. Some of these substances are bradykinin, prostaglandin E2 and serotonin. In the event of damage (noxa), these substances are released. If the concentration of these substances exceeds a certain level, then it results in a pain reaction. However, even if, on account of the concentration, the pain threshold is not exceeded, a small amount of these substances suffices to increase the excitability of the nociceptors. The nociceptors are then more sensitive and the person is more likely to perceive pain, and to a greater extent. The pain substances not only bring about sensitization of the nerve ends, they also have an effect on the permeability of the vessel walls and cause a narrowing of the blood vessels. The overall chemical environment of the nociceptor is changed and increases its excitability.
In particular, peptides perform important functions in the human body and also in the skin as bioactive messengers, for example, as hormones, neurotransmitters or as neuromodulators. The neuropeptide class of substances plays an important role since these are short oligopeptides which often occupy a position between hormones and pure neurotransmitters. The neuropeptide class of substances function is also referred to as neuromodulatory since they can gradually assist or suppress the effect of other transmitters. In contrast to molecularly small transmitters, synthesis and transport are rather slow and sluggish. In addition, neuropeptides do not bind directly to ion channels and thus do not change the tension of the postsynaptic membrane, but act via receptors upon cell functions and upon the cell structure of the postsynaptic target cell.
There is a large number of scientific investigations that concentrate on the role of oligopeptides as messengers and as neuromodulators in the brain. Thus, in immunological investigations, it has been established that when sensory nerve endings are stimulated, neuropeptides are released which are essential for neuronal perception and stimulus conveyance in the brain. Substance P is one example of such a neuropeptide which has become known primarily as a pain and inflammation mediator. Substance P consists of 11 amino acids and belongs to the group of neurokinins and is foiined by nerve cells, but also by leukocytes. The amino acid sequence is Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (SEQ ID NO:1).
If an afferent nociceptor is highly excited, it releases substance P, which was firstly recognized as a neurotransmitter in pain receptors and pain-conducting C fibers. However, substance P also plays a role as a modulator in inflammation reactions and brings about considerable dilation of the blood vessels and increases the permeability of the vessel walls. Consequently, local perfusion of the tissue is increased. These processes also bring about an increase in the sensitivity of the nociceptor.
The effect of capsaicin, the alkaloid occurring naturally in paprika and chili (which is in chemical terms is a vanillylamide of 8-methyl-6-nonanoic acid), is also based on the intense stimulation of chemonociceptors in nerve cells. Capsaicin stimulates the nerve ends of certain nociceptors which normally recognize pain stimuli upon the action of heat or chemical stimuli. Capsaicin binds to the TRP channel TRPV1, which is also activated through an increase in the temperature. The painful (but only apparent) heating due to capsaicin is counteracted by the organism through release of substance P from intracellular storage vesicles. This leads acutely to membrane depolarization and, as a result of the increased perfusion of the tissue for the purpose of dissipating heat, local reddening results, as in the case of a slight burn.
Substance P antagonists are at the moment very much the focus of scientific research, for example, for pain therapy and as potential antidepressants.
The effect of substance P in the synaptic gap is ended by rapid peptidase-mediated degradation. Protection against degradation by various endopeptidases can be achieved through enzyme inhibitors. This phenomenon is the subject of current pharmaceutical investigations. Various classes of substances are being investigated for this purpose. Besides other oligopeptides, in more recent medical investigations, two proline-containing pentapeptides with the sequence Val-Glu-Ile-Pro-Glu (SEQ ID NO:2) and Tyr-Pro-Ile-Pro-Phe (SEQ ID NO:3) have been identified. It is assumed that these are able to inhibit prolyl-endopeptidase. This enzyme is suspected of being involved in the pathogenesis of Alzheimer's disease and senility via the degradation of various neuropeptides.
Thus, for example, Yanai, Sato and Suzuki disclose, in Biosci. Biotechnol. Biochem., 67 (2), 380 to 382, 2003, oligopeptides with the sequences Val-Glu-Ile-Pro-Glu and Tyr-Pro-Ile-Pro-Phe which are suitable for inhibiting the prolylendopeptidase.
The use of certain peptides and oligopeptides as agents to counter external signs of skin aging in skincare products is known, for example, from the applications listed below.
WO 2005/048968 discloses the use of a combination of tri- and tetrapeptides in cosmetic compositions in order to alleviate or to avoid topically visible changes in the skin, such as wrinkles and dark circles. The combination of the peptides described in WO 2005/048968 reportedly results in an increased production of collagen I, fibronectin, collagen IV and hyaluronic acid in skin cells.
WO 2003/7068141 discloses a cosmetic or dermopharmaceutical composition for reducing symptoms of skin slackening and skin aging. This prior art composition comprises a synergistic combination of at least two, preferably three, components which are selected from    a) hesperidine or a derivative thereof    b) A.C.E. enzyme inhibitor dipeptides, and    c) oligopeptides R2-(AA)n-Pro-Arg-OH, where (AA)n is a peptide chain of amino acids or derivatives thereof,and n is between 1 and 3 and R2=H or an alkyl chain with C2 to C22.
In U.S. Pat. No. 5,492,894, an oligopeptide having 3 to 6 amino acids is used in a topical composition for the cosmetic treatment of wrinkles, where three of the amino acids are selected, independently of one another, from Lys or Arg.
In more recent cosmetic formulations for topical application to the skin, the oligopeptides used exhibit a muscle-relaxing effect and can thus reduce or eliminate mimic wrinkles, such as so-called crow's feet, in the skin. One example of this is a hexapeptide, acetyl hexapeptide-3 (argireline). This oligopeptide can inhibit the nerve signal to the muscle contraction, namely the messenger acetylcholine, and thus superficially relax and smooth the skin by interrupting stimulus conveyance. Such formulations are used as alternatives to antiwrinkle treatments with injections of the nerve poison botulinum toxin A (Botox).
However, all of the formulations of the cosmetic or dermatological skincare products known in the prior art are aimed at improving the external appearance of aging skin.
None of the described substances or formulations assists or improves the skin in its function as sensory organ such as, for example, by improving neuronal perception via the skin.
The estimation as to whether aging phenomena of the skin are to be perceived more as a consequence of a physiological process or as a disease state differs depending on the cultural, social and psychological background. The characteristic features of aging skin include atrophy, dryness, roughness, development of wrinkles, loss of elasticity, pigment irregularities, a tendency to form multiple, mostly benign, new growths and increased likelihood of injury as a result of extensive structural and functional changes, which ultimately lead to a thinning of the skin layers and to a decrease in their function-bearing components. Neuronal perception of the skin is also decisively impaired by aging processes. Thus, for example, thermoregulation in aged skin is increasingly sluggish, i.e., the protective organisms of the body against loss of heat or overheating no longer function to the extent that they used to in young skin. This is a result of the ever diminishing ability of the vessels to dilate or to constrict.